The innate ability of antibodies to bind their targets with high affinity and exquisite specificity is leveraged in the discovery of therapeutic antibodies to treat a broad range of diseases including cancer, autoimmune disease and heart disease.
In addition, antibodies are commonly used as companion diagnostics and reagents to support the therapeutic pipeline and to probe antigenic surfaces to inform vaccine design. Discovering antibodies with appropriate characteristics for a given purpose relies on their proper selection from the prolific number of clones that are routinely produced by modern antibody generation methods, including hybridoma technology in both normal and transgenic animals, phage display and synthetic libraries.
Triaging large panels of antibodies to a few leads is normally followed by substantial engineering to optimise their binding affinity, minimise immunogenicity and improve developability. This article reviews the current and emerging label-free biosensor tools that are used to characterise the binding interactions of antibodies in terms of their kinetics, affinities and epitope specificities from early stage screening to the clinic, with emphasis on throughput.
Within the animal kingdom, antibodies have evolved in jawed vertebrates (gnathostomes) to protect these organisms against pathogens and parasites (1). Antibodies bind their targets with high affinity and high specificity, which makes them appealing as both therapeutic agents and companion diagnostic reagents, and these products are generating lucrative sales in the pharmaceutical industry.
Antibodies are a class of specialised molecules produced and secreted by B lymphocytes in the immune system of an organism and their classical presentation is as a Y-shaped glycoprotein comprised of heavy and light polypeptide chains belonging to the immunoglobulin (Ig) superfamily of proteins. However, some species naturally produce other antibody formats, such as the small heavy chain-only fragments known as VHH or nanobodies in camelids (2) and the Ig new antigen receptor (IgNAR) in sharks (3).
Theoretical possibilities for unique-sequence antibodies are almost unlimited due to their architecture, where stretches of conserved framework residues descended from a limited set of germlines alternate with hypervariable ‘complementarydetermining regions’ (CDRs), which are responsible for the enormous sequence and structural diversity of an organism’s antibody repertoire.
While antibody generation in the pharmaceutical industry is highly commoditised, with modern in vivo and in vitro libraries typically producing vast numbers of clones, the analytical tools used to characterise their binding properties in terms of kinetics, affinity and specificity, which are key parameters for assessing their quality and functional activity, lag orders of magnitude behind in throughput.
With therapeutic antibodies being the largest class of biotherapeutic proteins that are in clinical trials, there is an ever-increasing demand for higher throughput analytical methods that can match the capacity of antibody production and guide the library-to-leads triage. Since taking an antibody from bench to the market is estimated to cost about $1 billion, there is a need to make antibody screening more efficient and comprehensive to cut costs and timelines....
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